The current proposal addresses the effect of exogenous female hormones on disease activity and severity in women with systemic lupus erythematosus (SLE). Oral contraceptives (OCs) and estrogen replacement therapy (ERT) are generally not prescribed due to the widely-held view that they can activate SLE. This practice is based on the greater incidence of SLE in women than in men, biologic abnormalities of estrogen metabolism, murine models of lupus, several anecdotes of patients having disease flares while receiving exogenous hormones, and a single retrospective study in patients with pre-existing renal disease. In contrast, recent retrospective studies suggest that the rate of flare is not significantly increased in patients taking OCs or ERT. The pre- existing data are insufficient to warrant the dismissal of a potentially important birth control option in a disease which predominantly affects women in their reproductive years and whose fertility is not altered by the disease. Moreover, the use of OCs to preserve fertility in patients taking cyclophosphamide, and the use of estrogens to prevent coronary artery disease and postmenopausal and steroid-induced osteoporosis are timely considerations. In Specific Aim 1 we will attempt to define, in a randomized double-blind placebo-controlled trial, the effect of OCs containing low dose synthetic estrogens and progestins on disease activity in women with SLE. Since the research hypothesis is that OCs do not increase the risk of flares, the study has been designed to be able to detect minimal increases in the rate of flares in patients taking OCs. Patients with inactive, stable or moderate disease requiring less than 0.5 mg prednisone per kg of bodyweight per day will be enrolled over a 2-year period and randomized to receive triphasic ethinylestradiol/ norethindrone or placebo for 12 months. In Specific Aim 2, we will) examine, in a randomized double-blind placebo-controlled trial, the effect of hormonal replacement with conjugated estrogens and cyclic low- dose medroxyprogesterone acetate on disease activity in postmenopausal women with SLE. Patients will be enrolled over 3 years and receive hormones for 1 year. This multicenter study represents a first-time clinical research collaboration between 5 major rheumatology centers: Hospital for Joint Diseases/Bellevue Hospital/New York University, Hospital for Special Surgery/Cornell University Medical, St. Luke's/Roosevelt Hospital Center, The Johns Hopkins Medical Center, and UCLA School of Medicine/LA County Harbor Medical Center. Patients will be recruited from the clinics and private practices which include over 4,000 women with SLE, most belonging to minority groups. The proposal embraces the cooperative efforts of rheumatology, reproductive endocrinology, epidemiology, and biostatistics, to initiate needed prospective controlled studies. Such approaches have already changed long-held beliefs about the risk of lupus flares during pregnancy.